Studies during the previous funding period dedicated to understanding the neurobiological basis of chronic vulnerability to relapse have provided important leads with regard to (a) differential effects of contextual stimuli conditioned to cocaine vs. potent natural reward in animal models of relapse where drug cues, but not non-drug cues, produce persistent, compulsive-like seeking behavior, and (b) the neural basis of this behavior. The objective of this proposal is to continue to study the neurobiological basis of chronic vulnerability to relapse with emphasis on identifying neural substrates responsible for the distinctly compulsive nature of cocaine-seeking, compared to behavior motivated by natural rewards essential for survival, well being, and healthy hedonic pursuits. These studies will be guided by (a) a priori hypotheses on a selective role of Group II metabotropic glutamate receptors (mGluR), the sigma1 (C1) receptor, as well the hypothalamic orexin/hypocretin (Orx/Hcrt) system and its projection to the paraventricular thalamus in the conditioned incentive effects of cocaine vs. natural reward, and (b) efforts to identify additional neural systems with a selective role in compulsive drug-seeking. Four major objectives will be pursued: (1) To pinpoint neuroanatomical substrates of the differential persistence of seeking behavior induced by stimuli conditioned to cocaine vs. highly palatable natural reward using immediate early gene neural mapping approaches; (2) to investigate the significance of Group II mGluR, C1 receptor, and Orx/Hcrt signaling in the regulating the persistence of seeking behavior associated with cocaine but not natural reward using quantitative immunohistochemistry and in situ hybridization; (3) to verify a role of Group II mGluR, C1, and Orx/Hcrt signaling within distinct brain regions in the persistence of seeking behavior induced by stimuli conditioned to cocaine vs. natural reward, using site-specific pharmacological manipulations; and (4) to establish whether neuroadaptation within the targeted neural systems associated with a history of cocaine exposure can convey compulsive character not only to drug-seeking behavior, but also behavior motivated by stimuli conditioned to natural reward. These studies will serve the additional important purpose of establishing whether drug-seeking behavior and behavior motivated by natural reward can be traced to the same neural systems and/or neuroadaptive changes during early (Specific Aim 1) vs. later (Specific Aim 4) cocaine abstinence phases. Drug addiction is a chronically relapsing disorder characterized by compulsive drug-seeking and use despite negative consequences. One manifestation of this drug compulsion is persistent vulnerability to relapse during abstinence. The proposed project will provide novel information on this critical aspect of drug compulsion at the basic science level that is expected to be relevant, ultimately, for the identification of novel treatment targets for cocaine dependence. This includes information relevant for novel therapeutic approaches aimed at enhancing the incentive salience of natural rewards to more effectively compete with and substitute for drug-derived reward.